Methods for therapeutic administration of messenger ribonucleic acid drugs

a messenger ribonucleic acid and drug technology, applied in the direction of drug composition, viruses/bacteriophages, immunological disorders, etc., can solve problems such as undesirable immune responses reduce or and inhibit accelerated blood clearance

Active Publication Date: 2018-09-13
MODERNATX INC
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  • Claims
  • Application Information

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Benefits of technology

[0028]In another embodiment, the disclosure provides a method of reducing or inhibiting accelerated blood clearance in a subject repeatedly administered a messenger RNA (mRNA) encoding a polypeptide of interest encapsulated in an lipid nanoparticle (LNP), the method comprising administering to the subject a chemically modified mRNA encoding the polypeptide of interest encapsulated in an lipid nanoparticle (LNP), wherein the chemically modified mRNA comprises at least one microRNA binding site for a microRNA expressed in immune cells, and wherein the chemically modified mRNA comprises one or more modified nucleobases, such that accelerated blood clearance is reduced or inhibited in the subject upon repeat administration.
[0029]In some embodiments, the disclosure provides a method of reducing or inhibiting accelerated blood clearance in a subject administered a messenger RNA (mRNA) encoding a polypeptide of interest encapsulated in an lipid nanoparticle (LNP), comprising administering to the subject intravenously a first dose of a chemically modified mRNA encapsulated in an lipid nanoparticle (LNP), wherein the chemically modified mRNA comprises at least one microRNA binding site for a microRNA expressed in immune cells, and wherein the chemically modified mRNA comprises one or more modified nucleobases; and administering to the subject intravenously a second dose of the chemically modified mRNA encapsulated in an LNP, such that accelerated blood clearance is reduced or inhibited in the subject.
[0030]In some embodiments, the disclosure provides a method of reducing or inhibiting production of IgM molecules that recognize polyethylene glycol (PEG) in a subject repeatedly administered a messenger RNA (mRNA) encoding a polypeptide of interest encapsulated in an lipid nanoparticle (LNP), the method comprising administering to the subject a chemically modified mRN...

Problems solved by technology

It has now been surprisingly discovered that administration to non-human primates of mRNA-based agents encoding a protein of interest can lead ...

Method used

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  • Methods for therapeutic administration of messenger ribonucleic acid drugs
  • Methods for therapeutic administration of messenger ribonucleic acid drugs
  • Methods for therapeutic administration of messenger ribonucleic acid drugs

Examples

Experimental program
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example 1

mRNA Encoding hEPO Elicits an Anti-Drug Antibody (ADA) Response in Non-Human Primates

[0428]In this example, modified mRNA (mmRNA) encoding human erythropoietin (hEPO), but lacking any miR binding sites, was administered to cynomolgus macaques in a four week study to examine expression of hEPO in the animals.

[0429]mmRNA encoding hEPO was formulated into MC3 lipid nanoparticles (LNP), which include MC3 50%, DSPC 10%, Cholesterol 38.5%, PEG-DMG 1.5%, N:P ˜5.5. (Values are based on mol. %). The mmRNA construct contained a Cap 1 5′ Cap structure (7mG(5′)ppp(5′)NlmpNp), was fully modified with 5-methylcytosine and 1-methylpseudouridine and comprised a 140 nucleotide poly A tail. The mmRNA construct lacked the presence of any inserted miR binding sites. The nucleotide sequence of this hEPO-encoding construct without any inserted miR binding sites is shown in SEQ ID NO: 7 (without the polyA tail shown).

[0430]The study comprised seven groups of animals. The negative control group was treated...

example 2

tion of an miR-142-3p Binding Site into mmRNA Inhibits an ADA Response to the Encoded Protein

[0436]In this example, a human EPO-encoding mmRNA construct was prepared that incorporated an miR-142-3p binding site into the 3′ UTR of the construct. The mmRNA construct comprised a Cap 1 5′ cap (7mG(5′)ppp(5′)NlmpNp), was fully modified with 5-methylcytosine and 1-methylpseudouridine and comprised a polyA tail of approximately 140 nucleotides. A schematic diagram of the construct is shown in FIG. 2. The nucleotide sequence of this human EPO-encoding mmRNA is shown in SEQ ID NO: 1 (without the poly A tail). The nucleotide sequence of the 3′ UTR comprising the miR-142-3p binding site is shown in SEQ ID NO: 2. The nucleotide sequence of the miR-142-3p binding site is shown in SEQ ID NO: 3. Other than the addition of the miR-142-3p binding site, the mmRNA construct and the LNP preparation were the same as in Example 1.

[0437]Cynomolgus macaque monkeys were treated with the construct comprising...

example 3

tion of an miR-126 or miR-142 Binding Site into mmRNA Inhibits B Cell Activation and Cytokine Expression

[0444]In this example, human EPO-encoding mmRNA constructs were prepared that incorporated either a miR-142-3p binding site or a miR-126-3p binding site, or both the miR-142-3p and miR-126-3p binding sites, into the 3′ UTR of the construct. The mmRNA constructs were administered to mice to examine the effects of incorporating the miR binding sites on various immune parameters in the mice.

[0445]The mmRNA constructs contained a Cap 1 5′ Cap structure (7mG(5′)ppp(5′)NlmpNp), were fully modified with 5-methylcytosine and 1-methylpseudouridine and comprised a 140 nucleotide poly A tail. The control mmRNA construct lacked the presence of any inserted miR binding sites. The nucleotide sequence of this control hEPO-encoding construct without any inserted miR binding sites is shown in SEQ ID NO: 7 (without the polyA tail shown). The nucleotide sequence of the hEPO-encoding construct with t...

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Abstract

The disclosure features methods of reducing or inhibiting an anti-drug antibody response in a subject, as well as methods of reducing or inhibiting unwanted immune cell activation in a subject to be treated with a messenger RNA (mRNA), comprising administering to the subject a mRNA, e.g., a chemically modified messenger RNA (mmRNA), encoding a polypeptide of interest, wherein the mRNA comprises at least one microRNA (miR) binding site for a miR expressed in immune cells, such as miR-126 binding site and/or miR-142 binding site, such that an anti-drug antibody response to the polypeptide or interest, or unwanted immune cell activation (e.g., B cell activation, cytokine secretion), is reduced or inhibited in the subject. The disclosure further provides therapeutic treatment regimens designed to reduce or inhibit AD A or unwanted immune cell activation (e.g., B cell activation, cytokine secretion) in a subject being treated with mRNA-based therapeutics.

Description

RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application Ser. No. 62 / 237,462 filed Oct. 5, 2015; U.S. Provisional Patent Application Ser. No. 62 / 317,268 filed Apr. 1, 2016; U.S. Provisional Patent Application Ser. No. 62 / 317,271 filed Apr. 1, 2016; U.S. Provisional Patent Application Ser. No. 62 / 317,366 filed Apr. 1, 2016; U.S. Provisional Patent Application Ser. No. 62 / 338,385 filed May 18, 2016; U.S. Provisional Patent Application Ser. No. 62 / 338,386 filed May 18, 2016; U.S. Provisional Patent Application Ser. No. 62 / 338,388 filed May 18, 2016; and U.S. Provisional Patent Application Ser. No. 62 / 350,149 filed Jun. 14, 2016. The entire contents of the above-referenced patent applications are incorporated herein by this reference.BACKGROUND OF THE INVENTION[0002]Biologics, such as recombinant antibodies, cytokines and growth factors, have been shown to be effective in the treatment of a wide variety of diseases and the FDA has now approved...

Claims

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Application Information

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IPC IPC(8): A61K31/7115C12N15/67A61K9/127A61K9/00C12N15/113C12N5/078C12N5/0784C12N5/0786C12N15/11
CPCA61K31/7115C12N15/67A61K9/127A61K9/0019C12N15/113C12N2310/141C12N2800/22C12N2800/107A61P37/06A61P43/00
Inventor HOGE, STEPHENCHAKRABORTY, TIRTHABESIN, GILLESJAIN, RUCHI
Owner MODERNATX INC
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